Colon Cancer Treatment (PDQ®)–Health Professional Version

General Information About Colon Cancer

Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of the patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.

Incidence and Mortality

Estimated new cases and deaths from colon cancer in the United States in 2016:[1]

Anatomy

Risk Factors

Groups that have a high incidence of colorectal cancer include those with hereditary conditions. Together, these groups account for 10% to 15% of colorectal cancers. These groups include the following:

These high-risk groups account for only 23% of all colorectal cancers. Limiting screening or early cancer detection to only these high-risk groups would miss the majority of colorectal cancers.[6] (Refer to the PDQ summaries on Colorectal Cancer Screening and Colorectal Cancer Prevention for more information.)

Screening

Because of the frequency of the disease, ability to identify high-risk groups, slow growth of primary lesions, better survival of patients with early-stage lesions, and relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer. (Refer to the PDQ summary on Colorectal Cancer Screening for more information.)

Prognostic Factors

The prognosis of patients with colon cancer is clearly related to the following:

The degree of penetration of the tumor through the bowel wall.

The presence or absence of nodal involvement.

The presence or absence of distant metastases.

These three characteristics form the basis for all staging systems developed for this disease.

Other prognostic factors include the following:

Bowel obstruction and bowel perforation are indicators of poor prognosis.[7]

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most, including allelic loss of chromosome 18q or thymidylate synthase expression, have not been prospectively validated.[9-18] Microsatellite instability, also associated with HNPCC, has been associated with improved survival independent of tumor stage in a population-based series of 607 patients younger than 50 years with colorectal cancer.[19] Patients with HNPCC reportedly have better prognoses in stage-stratified survival analysis than patients with sporadic colorectal cancer, but the retrospective nature of the studies and possibility of selection factors make this observation difficult to interpret.[20]

Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease, rather than the age of the patient.[21-23]

Racial differences in overall survival (OS) after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.[24]

Follow-up and Survivorship

Limited data and no level 1 evidence are available to guide patients and physicians about surveillance and management of patients after surgical resection and adjuvant therapy. The American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend specific surveillance and follow-up strategies.[25,26]

Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.[27-30] The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented an OS benefit for standard, postoperative monitoring program.[31-35]

CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:[36]

A CEA level is not a valuable screening test for colorectal cancer because of the large numbers of false-positive and false-negative reports.

Postoperative CEA testing should be restricted to patients who would be candidates for resection of liver or lung metastases.

Routine use of CEA levels alone for monitoring response to treatment should not be recommended.

The optimal regimen and frequency of follow-up examinations are not well defined because the impact on patient survival is not clear and the quality of data is poor.[33-35]

Factors Associated with Recurrence

Diet and exercise

No prospective randomized trials have demonstrated an improvement in outcome with a specific diet or exercise regimen; however, cohort studies suggest that diet or exercise regimen may improve outcome. The cohort studies contain multiple opportunities for unintended bias, and caution is needed when using the data from them.

Two prospective observational studies were performed with patients enrolled on CALGB-89803 (NCT00003835), which was an adjuvant chemotherapy trial for patients with stage III colon cancer.[37,38] In this trial, patients in the lowest quintile of the Western dietary pattern compared with those patients in the highest quintile experienced an adjusted hazard ratio (HR) for disease-free survival of 3.25 (95% confidence interval [CI], 2.04–5.19; P < .001) and an OS of 2.32 (95% CI, 1.36–3.96; P < .001). Additionally, findings included that stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted HR for OS of 1.76 (95% CI, 1.22–2.54; P < .001) compared with those in the lowest quintile. Subsequently, in the Cancer Prevention Study II Nutrition Cohort, among 2,315 participants diagnosed with colorectal cancer, the degree of red and processed meat intake before diagnosis was associated with a higher risk of death (relative risk [RR], 1.29; 95% CI, 1.05–1.59; P = .03), but red meat consumption after diagnosis was not associated with overall mortality.[39][Level of evidence: 3iiA]

A meta-analysis of seven prospective cohort studies evaluating physical activity before and after a diagnosis of colorectal cancer demonstrated that patients who participated in any amount of physical activity before diagnosis had a RR of 0.75 (95% CI, 0.65–0.87; P < .001) for colorectal cancer-specific mortality compared with patients who did not participate in any physical activity.[40] Patients who participated in a high amount of physical activity (vs. a low amount) before diagnosis had a RR of 0.70 (95% CI, 0.56–0.87; P = .002). Patients who participated in any physical activity (compared with no activity) after diagnosis had a RR of 0.74 (95% CI, 0.58–0.95; P = .02) for colorectal cancer-specific mortality. Those who participated in a high amount of physical activity (vs. a low amount) after diagnosis had a RR of 0.65 (95% CI, 0.47–0.92; P = .01).[40][Level of evidence: 3iiB]

Aspirin

A prospective cohort study examined the use of aspirin after a colorectal cancer diagnosis.[41] Regular users of aspirin after a diagnosis of colorectal cancer experienced an HR of colon cancer-specific survival of 0.71 (95% CI, 0.65–0.97) and an OS of 0.79 (95% CI, 0.65–0.97).[41][Level of evidence: 3iiA] One study evaluated 964 patients with rectal or colon cancer from the Nurse’s Health Study and the Health Professional Follow-up Study.[42] Among patients with PI3K-mutant colorectal cancer, regular use of aspirin was associated with an HR for OS of 0.54 (95% CI, 0.31–0.94; P = .01)[42][Level of evidence: 3iiiA]

Related Summaries

Other PDQ summaries containing information related to colon cancer include the following:

Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol 14 (10): 2843-77, 1996. [PUBMED Abstract]

References

Stage Information for Colon Cancer

Treatment decisions should be made with reference to the TNM classification [1] rather than to the older Dukes or the Modified Astler-Coller classification schema.

The American Joint Committee on Cancer (AJCC) and a National Cancer Institute–sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor.[2-4] This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.[5-8]

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM classification to define colon cancer.[1] The same classification is used for both clinical and pathologic staging.[1]

acTNM is the clinical classification, and pTNM is the pathologic classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (e.g., ypTNM). Patients who have a complete pathologic response (ypT0, N0, cM0) may be similar to stage group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease-free interval (rTNM).

bA satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumor Deposits.

eTis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

fDirect invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).

gTumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1–4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site-specific factor should be used for perineural invasion.

At a median follow-up of 4.4 years, 3-year recurrence rates (16% LAC vs. 18% open colectomy; hazard ratio [HR] for recurrence, 0.86; 95% confidence interval [CI], 0.63–1.17; P = .32) and 3-year overall survival (OS) rates (86% LAC vs. 85% open colectomy; HR for death in LAC, 0.91; 95% CI, 0.68–1.21; P = .51) were similar in both groups for all stages of disease evaluated. Tumor recurrence in surgical incisions was less than 1% for both groups.[5][Level of evidence: 1iiA]

Decreased hospital stay (5 days LAC vs. 6 days open colectomy, P < .001) and decreased use of analgesics were reported in the LAC group. A 21% conversion rate from LAC to open procedure was shown.

This study excluded patients with locally advanced disease, transverse colon and rectal tumor locations, and perforated lesions. Each of the 66 surgeons participating in the trial had performed at least 20 LACs and were accredited for study participation after independent videotape review assured appropriate oncologic and surgical principles were maintained.[5] The quality-of-life component of this trial was published separately and minimal short-term quality-of-life benefits with LAC were reported.[6][Level of evidence: 1iiC]

One small, single-institution randomized study of 219 patients showed that the LAC procedure was independently associated with reduced tumor recurrence on multivariate analysis.[7][Level of evidence: 1iiB]

Surgery is curative in 25% to 40% of highly selected patients who develop resectable metastases in the liver and lung. Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection.

Adjuvant Chemotherapy

The potential value of adjuvant chemotherapy for patients with stage II colon cancer is controversial. Pooled analyses and meta-analyses have suggested a 2% to 4% improvement in OS for patients treated with adjuvant fluorouracil (5-FU)–based therapy compared with observation.[8-10] (Refer to the Stage II Colon Cancer Treatment section of this summary for more information.)

Prior to 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Since 2000, capecitabine has been established as an equivalent alternative to 5-FU and leucovorin. The addition of oxaliplatin to 5-FU and leucovorin has been shown to improve OS compared with 5-FU and leucovorin alone. (Refer to the Stage III Colon Cancer Treatment section of this summary for more information.)

Adjuvant Radiation Therapy

While combined modality therapy with chemotherapy and radiation therapy has a significant role in the management of patients with rectal cancer (below the peritoneal reflection), the role of adjuvant radiation therapy for patients with colon cancer (above the peritoneal reflection) is not well defined. Patterns-of-care analyses and single-institution retrospective reviews suggest a role for radiation therapy in certain high-risk subsets of colon cancer patients (e.g., T4, tumor location in immobile sites, local perforation, obstruction, and residual disease postresection).[11-16]

Evidence (adjuvant radiation therapy):

Such observations led to the development of a phase III randomized intergroup study designed to test the benefit of adding radiation therapy to surgery and chemotherapy with 5-FU-levamisole for selected high-risk colon cancer patients (e.g., T4; or T3, N1–N2 ascending and/or descending colon).[17]

This clinical trial closed early secondary to inadequate patient accrual, and analysis of 222 enrolled patients (the original goal was 700 patients) demonstrated no relapse or OS benefit for the group receiving radiation therapy, though the sample size and statistical power were inadequate to exclude benefit.

Adjuvant radiation therapy has no current standard role in the management of patients with colon cancer following curative resection, although it may have a role for patients with residual disease.

Stage 0 Colon Cancer Treatment

Stage 0 colon cancer is the most superficial of all the lesions and is limited to the mucosa without invasion of the lamina propria. Because of its superficial nature, the surgical procedure may be limited.

Surgery

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
stage 0 colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage I Colon Cancer Treatment

Standard Treatment Options for Stage I Colon Cancer

Surgery

Standard treatment options for stage I colon cancer include the following:

Wide surgical resection and anastomosis.

Evidence (laparoscopic techniques):

The role of laparoscopic techniques [1-4] in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) with open colectomy.

The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[5][Level of evidence: 1iiC]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
stage I colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Standard Treatment Options for Stage II Colon Cancer

Surgery

The role of laparoscopic techniques [1-4] in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) to open colectomy.

The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[4][Level of evidence: 1iiC]

Treatment Options Under Clinical Evaluation

Adjuvant chemotherapy

The potential value of adjuvant chemotherapy for patients with stage II colon cancer remains controversial. Although subgroups of patients with stage II colon cancer may be at higher-than-average risk for recurrence (including those with anatomic features such as tumor adherence to adjacent structures, perforation, complete obstruction),[5-7] evidence is inconsistent that adjuvant 5-fluorouracil (5-FU)–based chemotherapy is associated with an improved OS compared with surgery alone.[8]

Features in patients with stage II colon cancer that are associated with an increased risk of recurrence include the following:

Inadequate lymph node sampling.

T4 disease.

Involvement of the visceral peritoneum.

A poorly differentiated histology.

The decision to use adjuvant chemotherapy for patients with stage II colon cancer is complicated and requires thoughtful consideration by both patients and their physicians. Adjuvant therapy is not indicated for most patients unless they are entered into a clinical trial.

Evidence (adjuvant chemotherapy):

The GRECCR-03 (NCT00046995) and NCRI-QUASAR1 (NCT00005586) trials evaluated the use of systemic or regional chemotherapy or biologic therapy. Following surgery, patients should be considered for entry into a carefully controlled clinical trial.

Investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP) have indicated that the reduction in risk of recurrence by adjuvant therapy in patients with stage II disease is of similar magnitude to the benefit seen in patients with stage III disease treated with adjuvant therapy, though an OS advantage has not been established.[9]

A meta-analysis of 1,000 stage II patients whose experience was amalgamated from a series of trials indicates a 2% advantage in disease-free survival at 5 years when adjuvant therapy–treated patients treated with 5-FU-leucovorin are compared with untreated controls.[10][Level of evidence: 1iiDii]; [11]

The Cancer Care Ontario Practice Guideline Initiative Gastrointestinal Cancer Disease Site Group undertook a meta-analysis of the English language–published literature consisting of randomized trials in which adjuvant chemotherapy was compared with observation for patients with stage II colon cancer.

Based on these data, the American Society of Clinical Oncology issued a guideline stating “direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer.”[13]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
stage II colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage III Colon Cancer Treatment

Stage III colon cancer denotes lymph node involvement. Studies have indicated that the number of lymph nodes involved affects prognosis; patients with one to three involved nodes have a significantly better survival than those with four or more involved nodes.

Surgery

The role of laparoscopic techniques [1-4] in the treatment of colon cancer was examined in a multicenter, prospective, randomized trial (NCCTG-934653 [NCT00002575]) comparing laparoscopic-assisted colectomy (LAC) with open colectomy.

The quality-of-life component of this trial has been published and minimal short-term quality-of-life benefits with LAC were reported.[5][Level of evidence: 1iiC]

Adjuvant chemotherapy

Chemotherapy regimens prior to 2000

Prior to 2000, 5-FU was the only useful cytotoxic chemotherapy in the adjuvant setting for patients with stage III colon cancer. Many of the early randomized studies of 5-FU in the adjuvant setting failed to show a significant improvement in survival for patients.[6-9] These trials employed 5-FU alone or 5-FU-semustine (methyl-CCNU).

A significant improvement in disease-free survival (DFS) was observed for patients with stage III colon cancer who received levamisole, but OS benefits were of borderline statistical significance.

An absolute survival benefit of approximately 12% (49% vs. 37%) was seen in patients with stage III disease treated with 5-FU-levamisole.

In a large confirmatory intergroup trial, 5-FU-levamisole prolonged DFS and OS in patients with stage III colon cancer compared with patients who received no treatment after surgery.[11][Level of evidence: 1iiA] Levamisole alone did not confer these benefits.

Subsequent studies tested the combination of 5-FU-leucovorin in the adjuvant treatment of patients with resected carcinoma of the colon.

Results of multiple randomized trials that have enrolled more than 4,000 patients comparing adjuvant chemotherapy with 5-FU-and leucovorin to surgery or 5-FU-semustine-vincristine demonstrate a relative reduction in mortality of between 22% and 33% (3-year OS of 71%–78% increased to 75%–84%).[12-14]

The completed Intergroup trial 0089 (INT-0089 [NCT00201331]) randomly assigned 3,794 patients with high-risk stage II or stage III colon cancer to one of the following four treatment arms:[15]

The Mayo Clinic regimen administered for a total of six cycles.

The Roswell Park regimen administered for a total of four cycles.

The Mayo Clinic regimen administered with levamisole for six cycles.

The Levamisole regimen administered for a total of 1 year.

Results:

Five-year OS ranged from 49% for the Mayo Clinic regimen with levamisole to 60% for the Mayo Clinic regimen, and there were no statistically significant differences among treatment arms.[15][Level of evidence: 1iiA]

A preliminary report in November 1997 demonstrated a statistically significant advantage for OS for the Mayo Clinic regimen with levamisole compared with the levamisole regimen. This difference became insignificant with longer follow-up.

Overall, grade 3 or greater toxicity occurred more frequently for the Mayo Clinic regimen and the Mayo Clinic regimen with levamisole. In addition, the Mayo Clinic regimen was significantly more toxic with levamisole than without levamisole.

The death rate for all four regimens ranged from 0.5% to 1%.

Because of its ease of use and its good toxicity profile, the Roswell Park regimen became the preferred adjuvant regimen used in the United States and was often the control arm in subsequent randomized studies.

In addition to INT-0089, multiple studies have refined the use of 5-FU-leucovorin in the adjuvant setting and can be summarized as follows:

A meta-analysis of seven trials revealed no significant difference in efficacy or toxicity among patients 70 years or younger compared with patients older than 70 years.[21]

An infusional deGramont LV5FU2 schedule is safer than a bolus modified Mayo Clinic schedule of 5-FU-leucovorin.[19]

Chemotherapy regimens after 2000

Capecitabine

Capecitabine is an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU with the last step occurring in the tumor cell. For patients with metastatic colon cancer, two studies have demonstrated the equivalence of capecitabine to 5-FU-leucovorin.[22,23]

A multicenter European study compared capecitabine (1,250 mg/m2) administered twice daily for days 1 to 14, then given every 21 days for eight cycles against the Mayo Clinic schedule of 5-FU and low-dose leucovorin for patients with stage III colon cancer.[24]

The study demonstrated that DFS at 3 years is equivalent for patients receiving capecitabine or 5-FU-leucovorin (hazard ratio [HR], 0.87; P < .001).[24][Level of evidence: 1iiDii]

Hand-foot syndrome and hyperbilirubinemia were significantly more common for patients receiving capecitabine, but diarrhea, nausea or vomiting, stomatitis, alopecia, and neutropenia were significantly less common.

Of patients receiving capecitabine, 57% required a dose modification.

For patients with stage III colon cancer in whom treatment with 5-FU-leucovorin is planned, capecitabine is an equivalent alternative.

Oxaliplatin

Oxaliplatin has significant activity when combined with 5-FU-leucovorin in patients with metastatic colorectal cancer.

Evidence (oxaliplatin):

In the 2,246 patients with resected stage II or stage III colon cancer in the completed Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC [NCT00275210]) study, the toxic effects and efficacy of FOLFOX-4 were compared with the same 5-FU-leucovorin regimen without oxaliplatin administered for 6 months.[25] Based on results from the MOSAIC trial, adjuvant FOLFOX-4 demonstrated prolonged OS for patients with stage III colon cancer compared with patients receiving 5-FU-leucovorin without oxaliplatin.[26]

The preliminary results of the study with 37 months of follow-up demonstrated a significant improvement in DFS at 3 years (77.8% vs. 72.9%; P = .01) in favor of FOLFOX-4. When initially reported, there was no difference in OS.[26][Level of evidence: 1iiDii]

Further follow-up at 6 years demonstrated that the OS for all patients (both stage II and stage III) entered into the study was not significantly different (OS = 78.5% vs. 76.0%; HR, 0.84; 95% confidence interval [CI], 0.71–1.00). On subset analysis, the 6-year OS in patients with stage III colon cancer was 72.9% in the patients receiving FOLFOX-4 and 68.7% in the patients receiving 5-FU-leucovorin (HR, 0.80; 95% CI, 0.65–0.97; P = .023).[26][Level of evidence: 1iiA]

FOLFOX has become the reference standard for the next generation of clinical trials for patients with stage III colon cancer.[26]

Treatment Options Under Clinical Evaluation

Eligible patients should be considered for entry into carefully controlled clinical trials comparing various postoperative chemotherapy regimens.[27]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
stage III colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage IV and Recurrent Colon Cancer Treatment

Stage IV colon cancer denotes distant metastatic disease. Treatment of recurrent colon cancer depends on the sites of recurrent disease demonstrable by physical examination and/or radiographic studies. In addition to standard radiographic procedures, radioimmunoscintography may add clinical information that may affect management.[1] Such approaches have not led to improvements in long-term outcome measures such as survival.

Treatment Options for Stage IV and Recurrent Colon Cancer

Treatment options for stage IV and recurrent colon cancer include the following:

Surgical resection of locally recurrent cancer.

Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases.

Resection of isolated pulmonary or ovarian metastases in selected patients.[12]

Palliative radiation therapy.

Palliative chemotherapy.

Targeted therapy.

Clinical trials evaluating new drugs and biological therapy.

Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

Treatment of Liver Metastasis

Approximately 50% of colon cancer patients will be diagnosed with hepatic metastases, either at the time of initial presentation or as a result of disease recurrence. Although only a small proportion of patients with hepatic metastases are candidates for surgical resection, advances in tumor ablation techniques and in both regional and systemic chemotherapy administration provide for a number of treatment options. These include the following:

Surgery

Hepatic metastasis may be considered to be resectable based on the following:[5,7,13-16]

Limited number of lesions.

Intrahepatic locations of lesions.

Lack of major vascular involvement.

Absent or limited extrahepatic disease.

Sufficient functional hepatic reserve.

For patients with hepatic metastasis that is considered to be resectable, a negative margin resection resulted in 5-year survival rates of 25% to 40% in mostly nonrandomized studies.[5,7,13-16] Improved surgical techniques and advances in preoperative imaging have allowed for better patient selection for resection. In addition, multiple studies with multiagent chemotherapy have demonstrated that patients with metastatic disease isolated to the liver, which historically would be considered unresectable, can occasionally be made resectable after the administration of chemotherapy.[17]

Neoadjuvant chemotherapy for unresectable liver metastases

Patients with hepatic metastases that are deemed unresectable will occasionally become candidates for resection if they have a good response to chemotherapy. These patients have 5-year survival rates similar to patients who initially had resectable disease.[17] There is no consensus on the best regimen to use to convert unresectable isolated liver metastases to resectable liver metastases.

Local ablation

Radiofrequency ablation has emerged as a safe technique (2% major morbidity and <1% mortality rate) that may provide for long-term tumor control.[18-24] Radiofrequency ablation and cryosurgical ablation [25-28] remain options for patients with tumors that cannot be resected and for patients who are not candidates for liver resection.

Other local ablative techniques that have been used to manage liver metastases include embolization and interstitial radiation therapy.[29,30] Patients with limited pulmonary metastases, and patients with both pulmonary and hepatic metastases, may also be considered for surgical resection, with 5-year survival possible in highly-selected patients.[12,31,32]

Adjuvant or neoadjuvant chemotherapy for resectable liver metastases

The role of adjuvant chemotherapy after potentially curative resection of liver metastases is uncertain.

In the era before the use of FOLFOX (folinic acid [LV], 5-fluorouracil [5-FU], and oxaliplatin) and FOLFIRI (5-FU and irinotecan), two trials attempted to randomly assign patients after resection of liver metastases to 5-FU/LV or observation, but both studies were closed early because of poor accrual.

The FFCD-9902 [NCT00304135] trial randomly assigned 173 patients (200 patients were planned) to postoperative 5-FU/LV, which is the Mayo Clinic regimen, or observation.[33]

The 5-year disease-free survival (DFS) rate was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio (OR) for recurrence or death, 0.66; 95% confidence interval [CI], 0.46–0.96; P = .028). The 5-year overall survival (OS) was not significantly different between the groups (chemotherapy group, 51.1% vs. the control group, 41.1%; ORdeath, 0.73; 95% CI, 0.48–1.10; P = .13).

The European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada/Gruppo Interdisciplinare Valutazione Interventi in Oncologia (EORTC/NCIC/GIVIO) International trial attempted a similar random assignment of patients after surgical resection of liver metastases. The study closed because of poor accrual, and a combined analysis of the study and the FFCD-9902 study was done instead. In the combined analysis, 278 patients (138 of whom received chemotherapy; 14 of whom received surgery alone) were included.[34]

Reversible postoperative complications occurred more often after chemotherapy than after surgery (40 [25%] of the 159 complications vs. 27 [16%] of the 170 complications; P = .04). After surgery, there were two deaths in the surgery-alone group and one in the perioperative chemotherapy group.

There is no level 1 evidence demonstrating that perioperative or postoperative chemotherapy improves OS for patients undergoing resection of liver metastases. Nevertheless, on the basis of post hoc subset analyses of the EORTC study, some physicians feel perioperative or postoperative therapy is reasonable in this setting.

Intra-arterial chemotherapy after liver resection

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has produced higher overall response rates but no consistent improvement in survival when compared with systemic chemotherapy.[2,37-41] A meta-analysis of the randomized studies, which were all done in the era when only fluoropyrimidines were available for systemic therapy, did not demonstrate a survival advantage.[42]

Evidence (intra-arterial chemotherapy after liver resection):

Two trials evaluated hepatic arterial floxuridine in the adjuvant setting after liver resection.

A second trial preoperatively randomly assigned 109 patients who had one to three potentially resectable colorectal hepatic metastases to either no further therapy or postoperative hepatic arterial floxuridine plus systemic 5-FU.[44] Of those randomly assigned patients, 27% were deemed ineligible at the time of surgery, which left only 75 patients evaluable for recurrence and survival.

While liver cancer recurrence was decreased, median or 4-year survival was not significantly different between the patient groups.

Further studies are required to evaluate this treatment approach and to determine whether more effective systemic combination chemotherapy alone may provide similar results compared with hepatic intra-arterial therapy plus systemic treatment.

Several studies show increased local toxic effects with hepatic infusional therapy, including liver function abnormalities and fatal biliary sclerosis.

Treatment of Stage IV and Recurrent Colon Cancer

Surgery

Treatment of patients with recurrent or advanced colon cancer depends on the location of the disease. For patients with locally recurrent and/or liver-only and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment.

Chemotherapy and targeted therapy

Currently, there are thirteen active U.S. Food and Drug Administration (FDA)-approved drugs for patients with metastatic colorectal cancer that are used alone and in combination with other drugs:

5-FU

When 5-FU was the only active chemotherapy drug, trials in patients with locally advanced, unresectable, or metastatic disease demonstrated partial responses and prolongation of the time-to-progression (TTP) of disease,[45,46] and improved survival and quality of life for patients who received chemotherapy versus best supportive care.[47-49] Several trials have analyzed the activity and toxic effects of various 5-FU/LV regimens using different doses and administration schedules and showed essentially equivalent results with a median survival time in the 12-month range.[50]

Capecitabine

Before the advent of multiagent chemotherapy, two randomized studies demonstrated that capecitabine was associated with equivalent efficacy when compared with the Mayo Clinic regimen of 5-FU/LV.[51,52][Level of evidence: 1iiA]

Irinotecan

Three randomized studies demonstrated improved response rates, PFS, and OS when irinotecan or oxaliplatin was combined with 5-FU-leucovorin.[53-55]

Subsequently, two studies compared FOLFOX with LV/5-FU/irinotecan (FOLFIRI), and patients were allowed to cross over upon progression on first-line therapy, respectively.[56,57][Level of evidence: 1iiDiii]

PFS and OS were identical between the treatment arms in both studies.

The Bolus, Infusional, or Capecitabine with Camptosar-Celecoxib (BICC-C [NCT00094965]) trial evaluated several different irinotecan-based regimens in patients with previously untreated metastatic colorectal cancer, including FOLFIRI, mIFL, and Capecitabine/irinotecan (CAPIRI).[58][Level of evidence: 1iiA]

The study randomly assigned 430 patients and was closed early because of poor accrual.

The patients who received FOLFIRI had a better PFS than the patients who received either mIFL (7.6 months vs. 5.9 months, P = .004) or CAPIRI (7.6 months vs. 5.8 months, P = .015).

Patients who received CAPIRI had the highest grade 3 or higher rates of nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome.

Since the publication of these studies, the use of either FOLFOX or FOLFIRI is considered acceptable for first-line treatment of patients with metastatic colorectal cancer.

When using an irinotecan-based regimen as first-line treatment of metastatic colorectal cancer, FOLFIRI is preferred.[58][Level of evidence: 1iiDiii]

When using an oxaliplatin-based regimen as first-line treatment of metastatic colorectal cancer, a CAPOX regimen is not inferior to a FUOX regimen.

Before the availability of cetuximab, panitumumab, bevacizumab, and aflibercept as second-line therapy, second-line chemotherapy with irinotecan in patients treated with 5-FU/LV as first-line therapy demonstrated improved OS when compared with either infusional 5-FU or supportive care.[61-64]

Bevacizumab

Bevacizumab is a partially humanized monoclonal antibody that binds to vascular endothelial growth factor. Bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer.

Evidence (bevacizumab):

After bevacizumab was approved, the BICC-C trial was amended, and an additional 117 patients were randomly assigned to receive FOLFIRI/bevacizumab or mIFL/bevacizumab.

Although the primary endpoint of PFS was not significantly different, patients who received FOLFIRI/bevacizumab had a significantly better OS (not yet reached with a median follow-up of 22.6 months vs. 19.2 months, P = .007).

Patients with previously untreated metastatic colorectal cancer were randomly assigned to either IFL or IFL/bevacizumab.[66][Level of evidence: 1iiA]

The patients randomly assigned to IFL/bevacizumab experienced a significantly better PFS (10.6 months in the group given IFL/bevacizumab, as compared with 6.2 months in the group given IFL/placebo; HR for disease progression, 0.54; P < .001) and OS (20.3 months in the group given IFL/ bevacizumab, as compared with 15.6 months in the group given IFL/ and placebo corresponding to an HR for death, 0.66; P < .001).[66]

Despite the lack of direct data, in standard practice, bevacizumab was added to FOLFOX as a standard first-line regimen based on the results of the NCCTG-N9741 trial.[67] Subsequently, in a randomized phase III study, patients with untreated, stage IV, colorectal cancer were randomly assigned in a 2 × 2 factorial design to CAPOX versus FOLFOX-4, then to bevacizumab versus placebo. PFS was the primary endpoint.

Based on these studies, bevacizumab can reasonably be added to either FOLFIRI or FOLFOX for patients undergoing first-line treatment of metastatic colorectal cancer. A major question was whether the use of bevacizumab after first-line therapy was warranted when bevacizumab was used as a component of first-line therapy. At the 2012 American Society of Clinical Oncology Annual Meeting, data were presented from a randomized, controlled trial.[71] In the trial, 820 patients with metastatic colorectal cancer, after progressing on first-line chemotherapy that included bevacizumab, were randomly assigned to chemotherapy without bevacizumab or chemotherapy with bevacizumab. Patients who received bevacizumab experienced an improved OS compared with the patients who did not receive bevacizumab. Median OS was 11.2 months for patients who received bevacizumab plus chemotherapy and 9.8 months for patients who received chemotherapy without bevacizumab (HR, 0.81; 95% CI, 0.69–0.94; unstratified log-rank test, P = .0062). Median PFS was 5.7 months for patients who received bevacizumab plus chemotherapy and 4.1 months for those who received chemotherapy without bevacizumab (HR, 0.68; 95% CI, 0.59–0.78; unstratified log-rank test, P < .0001). [71][Level of evidence: 1iiA]

FOLFOXIRI

Evidence (FOLFOXIRI):

The combination of FOLFOXIRI with bevacizumab was compared with FOLFIRI with bevacizumab in a randomized, phase III study of 508 patients with untreated metastatic colorectal cancer.[72][Level of evidence: 1iiDiii]

Patients who received FOLFOXIRI had significantly more grade 3 and 4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy.

Cetuximab

Cetuximab is a partially humanized monoclonal antibody against the EGFR. Because cetuximab affects tyrosine kinase signaling at the surface of the cell membrane, tumors with mutations causing activation of the pathway downstream of the EGFR, such as KRAS mutations, are not sensitive to its effects. The addition of cetuximab to multiagent chemotherapy improves survival in patients with colon cancers that lack a KRAS mutation (i.e., KRAS wild type). Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

Evidence (cetuximab):

For patients who have progressed on irinotecan-containing regimens, a randomized, phase II study was performed of either cetuximab or irinotecan and cetuximab.[73][Level of evidence: 3iiiDiv]

The median TTP for patients who received cetuximab was 1.5 months, compared with the median TTP of 4.2 months for patients receiving irinotecan and cetuximab.[73][Level of evidence: 1iiDiii]

On the basis of this study, cetuximab was approved for use in patients with metastatic colorectal cancer refractory to 5-FU and irinotecan.

The addition of cetuximab was associated with an improved PFS (HR, 0.85; 95% CI, 0.72–0.99; P = .048, by a stratified log rank test) but not OS.

Retrospective studies of patients with metastatic colorectal cancer have suggested that responses to anti-EGFR antibody therapy are confined to patients with tumors that harbor wild types of KRAS (i.e., lack activating mutations at codon 12 or 13 of the KRAS gene).

A subset analysis evaluating efficacy vis-à-vis KRAS status was done in patients enrolled on the Crystal Study. There was a significant interaction for KRAS mutation status and treatment for tumor response (P = .03) but not for PFS (P = .07). Among patients with KRAS wild-type tumors, the HR favored the FOLFIRI/cetuximab group (HR, 0.68; 95% CI, 0.50–0.94).

In a randomized trial, patients with metastatic colorectal cancer received capecitabine/oxaliplatin/bevacizumab with or without cetuximab.[75][Level of evidence: 1iiDiii]

The median PFS was 9.4 months in the group who received cetuximab and 10.7 months in the group who did not receive cetuximab (P = .01).

The Medical Research Council (MRC) (COIN [NCT00182715] trial) sought to answer the question of whether adding cetuximab to combination chemotherapy with a fluoropyrimidine and oxaliplatin in first-line treatment for patients with first-line KRAS wild-type tumors was beneficial.[76,77]

In addition, the MRC sought to evaluate the effect of intermittent chemotherapy versus continuous chemotherapy. The 1,630 patients were randomly assigned to three treatment groups:

Arm A: fluoropyrimidine/oxaliplatin.

Arm B: fluoropyrimidine/oxaliplatin/cetuximab.

Arm C: intermittent fluoropyrimidine/oxaliplatin.

The comparisons between arms A and B and arms A and C were analyzed and published separately.[76,77]

The reasons for lack of benefit in adding cetuximab are unclear. Subset analyses suggest that the use of capecitabine was associated with an inferior outcome, and the use of second-line therapy was less frequent in patients treated with cetuximab.

There was no difference between the continuously treated patients (arm A) and the intermittently treated patients (arm C). Median survival in the intent-to-treat population (n = 815 in both groups) was 15.8 months (IQR, 9.4–26.1) in arm A and 14.4 months (IQR, 8.0–24.7) in arm C (HR, 1.084; 80% CI, 1.008–1.165). In the per-protocol population, which included only those patients who were free from progression at 12 weeks and randomly assigned to continue treatment or go on a chemotherapy holiday (arm A, n = 467; arm C, n = 511), median survival was 19.6 months (IQR, 13.0–28.1) in arm A and 18.0 months (IQR, 12.1–29.3) in arm C (HR, 1.087; 95% CI, 0.986–1.198). The upper limits of CIs for HRs in both analyses were greater than the predeﬁned noninferiority boundary. While intermittent chemotherapy was not deemed noninferior, there appeared to be clinically insignificant differences in patient outcomes.

The OPUS study sought to evaluate the effect of adding cetuximab to first-line treatment with a FOLFOX regimen in an open-labeled, randomized, multicenter, phase II study of patients with EGFR-expressing metastatic colorectal cancer.[78]

In the trial, 344 patients were randomly assigned to receive FOLFOX-4 alone or FOLFOX-4 plus cetuximab. There was no statistically significant difference in response rate or PFS.

On the basis of these results, the use of FOLFIRI plus aflibercept is an acceptable second-line regimen for patients previously treated with FOLFOX-based chemotherapy. Whether to continue bevacizumab or initiate aflibercept in second-line therapy has not been addressed as yet in any clinical trial, and there are no data available.

Ramucirumab

In the randomized, unblinded, phase III RAISE (NCT01183780) study, 1,072 patients with stage IV colorectal cancer who had progressed on first-line chemotherapy were randomly assigned to FOLFIRI with or without ramucirumab (8 mg/kg).[80][Level of evidence: 1iiA]

Grade 3 adverse events were more common in the ramucirumab group, including grade 3 neutropenia.

On the basis of this data, FOLFIRI plus ramucirumab is an acceptable second-line regimen for patients previously treated with FOLFOX-bevacizumab. Whether to continue bevacizumab in second-line chemotherapy or use ramucirumab in second-line chemotherapy has not yet been addressed in a clinical trial.

Panitumumab

Panitumumab is a fully humanized antibody against the EGFR. The FDA approved panitumumab for use in patients with metastatic colorectal cancer refractory to chemotherapy.[81] In clinical trials, panitumumab demonstrated efficacy as a single agent or in combination therapy, which was consistent with the effects on PFS and OS with cetuximab. There appears to be a consistent class effect.

Evidence (panitumumab):

In a phase III trial, patients with chemotherapy-refractory colorectal cancer were randomly assigned to panitumumab or best supportive care.[81][Level of evidence: 1iiDiii]

There was no difference in OS, which was thought to be the result of 76% of patients on best supportive care crossing over to panitumumab.

In the Panitumumab Randomized Trial in Combination With Chemotherapy for
Metastatic Colorectal Cancer to Determine Efficacy (PRIME) [NCT00364013] study, 1,183 patients were randomly assigned to FOLFOX-4 with or without panitumumab as first-line therapy for metastatic colorectal cancer. The study was amended to enlarge the sample size to address patients with the KRAS wild-type tumors and patients with mutant KRAS tumors separately.[82][Level of evidence: 1iiDiii]

For patients with KRAS wild-type tumors, a statistically significant improvement in PFS was observed in those who received panitumumab/FOLFOX-4 compared with those who received only FOLFOX-4 (HR, 0.80; 95% CI, 0.66–0.97; P = .02, stratified log-rank test).

Of the 620 patients who were initially identified as not having a mutation in exon 2 of KRAS, 108 patients (17%) were found to have additional RAS mutations and 53 patients (8%) were found to have BRAF mutations. In a retrospective analysis, patients without any RAS or BRAF mutations had a longer PFS (10.8 months vs. 9.2 months, P = .002) and OS (28.3 months vs. 20.9 months, P = .02) when assigned to the FOLFOX-4/panitumumab arm than the patients assigned to the FOLFOX-4 arm.

Similarly, the addition of panitumumab to a regimen of FOLFOX/bevacizumab resulted in a worse PFS and worse toxicity compared with a regimen of FOLFOX/bevacizumab alone in patients not selected for KRAS mutation in metastatic colon cancer (11.4 months vs. 10.0 months, HR, 1.27; 95% CI, 1.06–1.52).[84][Level of evidence: 1iiDiii]

In another study (NCT00339183), patients with metastatic colorectal cancer who had already received a fluoropyrimidine regimen were randomly assigned to either FOLFIRI or FOLFIRI plus panitumumab.[85][Level of evidence: 1iiDiii]

In the management of patients with stage IV colorectal cancer, it is unknown whether patients with KRAS wild-type cancer should receive an anti-EGFR antibody with chemotherapy or an anti-VEGF antibody with chemotherapy. Two studies attempted to answer this question.[86,87]

On the basis of these two studies, no apparent significant difference is evident about starting treatment with chemotherapy/bevacizumab or chemotherapy/cetuximab in patients with KRAS wild-type metastatic colorectal cancer. However, in patients with KRAS wild-type cancer, administration of an anti-EGFR antibody at some point in the course of management improves OS.

Regorafenib

Regorafenib is an inhibitor of multiple tyrosine kinase pathways including VEGF. In September 2012, the FDA granted approval for the use of regorafenib in patients who had progressed on previous therapy.

Evidence (regorafenib):

The safety and effectiveness of regorafenib were evaluated in a single, clinical study of 760 patients with previously treated metastatic colorectal cancer. Patients were randomly assigned in a 2:1 fashion to receive regorafenib or a placebo in addition to the best supportive care.[89,90]

TAS-102

TAS-102 (Lonsurf) is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Trifluridine, in its triphosphate form, inhibits thymidylate synthase; therefore, trifluridine, in this form, has an anti-tumor effect. Tipiracil hydrochloride is a potent inhibitor of thymidine phosphorylase, which actively degrades trifluridine. The combination of trifluridine and tipiracil allows for adequate plasma levels of trifluridine.

Evidence (TAS-102):

A phase III, double-blind study (RECOURSE [NCT01607957]) randomly assigned 800 stage IV colorectal cancer patients whose cancer had been refractory to two previous therapies. Patients were required to have received 5-FU, oxaliplatin, irinotecan, bevacizumab and, if the patients had KRAS wild-type cancer, cetuximab or panitumumab. Patients were randomly assigned in a 2:1 ratio to receive best supportive care plus TAS-102 (n = 534) or placebo (n = 266). The median age of patients was 63 years, and the majority of patients (60%–63%) received four or more previous lines of therapy. All patients had formerly received fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and 52% of them had received an EGFR inhibitor. Approximately 20% of the patients had received previous treatment with regorafenib.[91][Level of evidence: 1iiA]

TAS-102 was administered at 35 mg/m2 twice daily with meals for 5 days, with 2 days of rest for 2 weeks, followed by a 14-day rest period.

The primary endpoint of the study was OS. The median OS for patients with metastatic colorectal cancer who received TAS-102 was 7.1 months compared with 5.3 months for those who received a placebo (HR, 0.68; P < .0001).

The median PFS time in the TAS-102 arm was 2 months versus 1.7 months with a placebo (HR, 0.48; P < .0001).

The overall response rate was 1.6% with TAS-102, which consisted of a complete response in one patient and partial responses in other patients. The overall response rate with a placebo was 0.4% (P = .29).

TAS-102 was approved by the FDA for the treatment of metastatic colorectal cancer patients, based on the results of the RECOURSE trial.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for stage IV and recurrent colon cancer include the following:

Clinical trials evaluating new drugs and biological therapy.

Clinical trials comparing various chemotherapy regimens or biological therapy, alone or in combination.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with
stage IV colon cancer and recurrent colon cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of colon cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Colon Cancer Treatment are:

Russell S. Berman, MD (New York University School of Medicine)

David P. Ryan, MD (Massachusetts General Hospital)

Jennifer Wo, MD (Massachusetts General Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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Updated: August
12, 2016

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